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Biochim Biophys Acta Mol Cell Res. 2018 Nov;1865(11 Pt B):1718-1732. doi: 10.1016/j.bbamcr.2018.08.003. Epub 2018 Aug 9.

Intracellular calcium dysregulation in autism spectrum disorder: An analysis of converging organelle signaling pathways.

Author information

1
Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA; UCI Center for Autism Research and Translation, School of Medicine, University of California, Irvine, Irvine, CA, USA.
2
Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA; UCI Center for Autism Research and Translation, School of Medicine, University of California, Irvine, Irvine, CA, USA; Department of Neurology, University of California, Irvine, Irvine, CA, USA.
3
UCI Center for Autism Research and Translation, School of Medicine, University of California, Irvine, Irvine, CA, USA.
4
Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA; UCI Center for Autism Research and Translation, School of Medicine, University of California, Irvine, Irvine, CA, USA; Department of Pediatrics, Section of Human Genetics and Genomics, University of California, Irvine, Irvine, CA, USA. Electronic address: jjgargus@uci.edu.

Abstract

Autism spectrum disorder (ASD) is a group of complex, neurological disorders that affect early cognitive, social, and verbal development. Our understanding of ASD has vastly improved with advances in genomic sequencing technology and genetic models that have identified >800 loci with variants that increase susceptibility to ASD. Although these findings have confirmed its high heritability, the underlying mechanisms by which these genes produce the ASD phenotypes have not been defined. Current efforts have begun to "functionalize" many of these variants and envisage how these susceptibility factors converge at key biochemical and biophysical pathways. In this review, we discuss recent work on intracellular calcium signaling in ASD, including our own work, which begins to suggest it as a compelling candidate mechanism in the pathophysiology of autism and a potential therapeutic target. We consider how known variants in the calcium signaling genomic architecture of ASD may exert their deleterious effects along pathways particularly involving organelle dysfunction including the endoplasmic reticulum (ER), a major calcium store, and the mitochondria, a major calcium ion buffer, and theorize how many of these pathways intersect.

KEYWORDS:

Autism spectrum disorder; Calcium; Endoplasmic reticulum; IP(3) signaling; Intracellular calcium signaling; Organellar disease

PMID:
30992134
DOI:
10.1016/j.bbamcr.2018.08.003
[Indexed for MEDLINE]
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